Synthesis of chlorinated pyrimidines

ABSTRACT

The invention provides a process for synthesizing chlorinated pyrimidines. The process includes reacting imidoyl chloride compounds with phosgene (COCl 2 ). The imidoyl chloride compounds can be supplied as starting materials or can be produced by reacting organic amides with phosgene or reacting organic nitrites with hydrogen chloride. Phosgene may be replaced by equivalent reagents. The chlorinated pyrimidines, such as 4,6-dichloropyrimidine, can be used to synthesize other compounds useful in a variety of compositions, such as fungicides, pesticides, and pharmaceuticals.

This application is a continuation-in-part of U.S. application Ser. No.09/876,964, filed on Aug. 6, 2001 now U.S. Pat. No. 6,608,199.

FIELD OF THE INVENTION

This invention relates to the field of organic compounds. Moreparticularly, this invention relates to the synthesis of certainchlorinated pyrimidines such as 4,6-dichloro-pyrimidine. In general,synthesis of chlorinated pyrimidines according to the present inventionis accomplished by reacting imidoyl chlorides with phosgene.

DESCRIPTION OF RELATED ART

Chlorinated pyrimidines prepared by the process of the present inventionand, in particular 4,6-dichloropyrimidine, are known as useful compoundsin the synthesis of many biologically active compounds. Use of suchchlorinated pyrimidines in production of such varied compositions aspesticides and pharmaceuticals makes them economically importantcompounds as well. For example, 4,6-dichloropyrimidine can be used inthe manufacture of azoxystrobin, a methoxyacrylate-type fungicide.Because of their wide use and economic importance, many methods ofsynthesis of chlorinated pyrimidines, especially 4,6-dichloropyrimidine,have been developed.

For example, U.S. Pat. No. 6,018,045 to Whitton et al. discloses aprocess for preparing 4,6-dichloropyrimidine that comprises treating4,6-dihydroxyprimidine with phosphorous oxychloride (phosphorylchloride) in the presence of a saturated hindered amine, thehydrochloride salt of a saturated hindered amine, or an unsaturated5-membered nitrogen containing ring, or a mixture thereof. As a furtherstep, the 4,6-dichloro-pyrimidine formed from these reactions is firstdirectly extracted by, for example, a counter-current liquid-liquidseparation technique. The process may also include mixing the residuethat remains after the direct extraction with an aqueous solution ofsodium or potassium hydroxide in order to liberate the saturatedhindered amine or unsaturated 5-member nitrogen-containing ring (ormixture thereof), that was used in the process.

Other disclosures generally relating to preparation of4,6-dichloropyrimidine by reacting 4,6-dihydroxyprimidine withphosphorous oxychloride in the presence of a suitable base includeKenner et al. (J. CHEM. SOC., November 1943, pp. 574—574), Hull (J.CHEM. SOC., August 1951, p. 2214), British Patent GB2287466, and U.S.Pat. No. 5,583,226 to Stucky et al. In addition, U.S. Pat. No. 5,677,453to Cramm et al. discloses synthesis of 4,6-dichloropyrimidines byreacting 4,6-dihydroxypyrimidines with excess phosphoryl chloride. Inthis type of synthesis, no base is added; however, an excess ofphosphorus and chloride is used (with respect to the4,6dihydroxypyrimidines). This excess is maintained by adding phosphorustrichloride and chlorine to the reaction mixture in amounts such thatthe phosphorus trichloride is maintained in excess over the chlorine.The process is carried out at temperatures of 60-110° C. Distillation isadvantageously used to purify the 4,6-dichloropyrimidines.

Further, U.S. Pat. No. 5,570,694 to Jones et al. and WO 95/29166 (ZenecaLimited) disclose that 4,6-dichloropyrimidine can be prepared byreacting 4,6-dihydroxypyrimidine with phosgene (carbonyl chloride;carbon oxychloride; COCl₂) in the presence of a suitable base. The baseis preferably a tertiary amine and the base-to-phosgene ratio ispreferably in the range of 10:1 to 1:10. Preferably, the process iscarried out in a solvent or a mixture of solvents, with chlorinatedsolvents, ethers, and polar aprotic solvents being most preferred.

Yanagida et al. (J. ORG. CHEM. 34(10):2972-2975, 1969) disclosepreparation of specific 2,5-disubstituted-4,6-dichloropyrimidines byreacting an aliphatic nitrile compound of the general formula RCH₂CNwith itself in the presence of HCl and COCl₂. According to the synthesisof Yanagida et al., R can be H, CH₃, CH₃CH₂, CH₃(CH₂)₂, CH₂(CH₂)₃, (CHCl(CH₂)₂, or CH₃CH₂O(CH₂)₂. The authors propose a reaction scheme inwhich 2,5-disubstituted-4,6-dichloropyrimidine synthesis proceedsthrough a 6-chloro-2,5-disubstituted-4(3H)pyrimidone intermediate.Further reaction of these intermediates with phosgene gives thecorresponding 2,5-disubstituted-4,6-dichloropyrimidines. The authorsalso propose a second reaction scheme for formation of2,5-disubstituted-4,6-dichloropyrimidines from aliphatic nitrites. Inthe second scheme an aliphatic nitrile condenses with itself in thepresence of HCl to form an amidine, which is then converted in thepresence of phosgene to ultimately give a2,5-disubstituted-4,6-dichloropyrimidine. Further, Yanagiida et al. (J.BULL. CHEM. SOC. JAPAN 46:299-302, 1973) discloses reaction ofN-(α-chloroalkenyl)alkylamidine hydrochlorides with phosgene to create4,6-dichloro-2,5-disubstituted pyrimidines.

However, none of these latter references discloses the preparation ofchlorinated pyrimidines that are not substituted in the 2 position,including 4,6-dichloropyrimidine itself. Synthesis of chlorinatedpyrimidines that are not substituted in the 2-position requirescross-condensation of two distinct imidoyl chloride compounds, with oneof the imidoyl chloride components being derived from either hydrogencyanide or formamide or a substituted replacement, such as ethylcyanoformate, wherein the substituent can be converted to the requisitehydrogen which ends up in the 2 position. For the purposes of thefollowing discussions, where hydrogen cyanide or formamide or theirderivatives (imidoyl chlorides) are considered, it will be understoodthat such substituted replacements and their analogous derivatives aresimilarly included. Such replacements are discussed and exemplifiedbelow. The conversion of amides to imidoyl chlorides may be accomplishedusing phosgene, the central carbon of which is also incorporated intothe molecule during the further conversion of the imidoyl chlorides topyrimidines and which is also required for the final conversion of theintermediate pyrimidinol to the product 4,6-dichloropyrimidine or its5-substituted analogues. Replacements for phosgene in the conversion ofamides to imidoyl chlorides and in the incorporation of a 1 carbonfragment into a molecule and in conversion of heteroarylhydroxy groupsto heteroaryl chlorides are known. For the purposes of the followingdiscussions, where phosgene (COCl₂) is considered, it will be understoodthat such phosgene replacements are similarly included. Suchreplacements are discussed and exemplified below.

Because of the economic importance of 4,6-dichloropyrimidine in theproduction of agricultural and medical compounds, as well as itsimportance in production of tools for scientific research, new,straightforward, rapid, and cost-effective methods for synthesis of thischlorinated pyrimidine are continually being developed.

SUMMARY OF THE INVENTION

The present invention provides a method of synthesizing4,6-dichloropyrimidine, 4-chloro-6hydroxypyrimidine,5-substituted-4-chloro-6-hydoxypyrimidines, and5-substituted-4,6-dichloropyrimidines. The method is less expensive andsimpler than those methods currently available. In general, the methodof preparing these compounds according to the present inventioncomprises cross-condensation of formamidoyl chloride with a distinctimidoyl chloride compound in the presence of phosgene (COCl₂) and HCland, optionally, in the presence of solvent. For present purposes,“distinct imidoyl chloride compound” refers to compounds with differenthydrocarbyl groups, preferably different alkyl groups, than formamidoylchloride, for example, acetamidoyl chloride. The present invention alsoincludes use of compounds that can be easily converted into imidoylchlorides under reaction conditions, for example, nitriles likeacetonitrile which react with HCl to give the imidoyl chloride. In thecase of formamidoyl chloride, the starting materials can optionally behydrogen cyanide and HCl; or formamide and phosgene; or analogues ofhydrogen cyanide and formamide in which the hydrogen bound to carbon isreplaced with a substituent that can be converted to H. Thesesubstituents include, but are not limited to, C₁₋₄ alkoxycarbonyl, C₁₋₄alkoxysulfinyl, trimethylsilyl and a group C(OH)R′R″ where R′ and R″ areindependently H, C₁₋₄ alkyl or phenyl. The present invention alsoincludes the use of compounds in place of phosgene that are known toreact similarly, such as diphosgene, triphosgene and oxalyl chloride.

In one embodiment, the synthesis method of the present inventionincludes cross-condensation of imidoyl chloride compounds derived from anitrile and hydrogen cyanide. For example, the method of the inventioncan include reacting acetonitrile and hydrogen cyanide with hydrogenchloride and phosgene to form 4,6-dichloropyrimidine.

In other embodiments of the invention, the method includescross-condensation of imidoyl chloride compounds derived from analkylamide and hydrogen cyanide. For example, the method of theinvention can include reacting acetamide and hydrogen cyanide withhydrogen chloride and phosgene to form 4,6-dichloropyrimidine.

In further embodiments of the invention, the method includescross-condensation of imidoyl chloride compounds derived from a nitrileand formamide. For example, the method of the invention can includereacting acetonitrile and formamide with hydrogen chloride and phosgeneto form 4,6-dichloropyrimidine.

In other embodiments of the invention, the method includescross-condensation of imidoyl chloride compounds derived from analkylamide and formamide. For example, the method of the invention caninclude reacting acetamide and formamide with hydrogen chloride andphosgene to form 4,6-dichloropyrimidine.

In each of these embodiments, the method includes the use of phosgenereplacements in place of phosgene. An example of such a phosgenereplacement is diphosgene (ClCO₂CCl₃). Likewise, in each of theseembodiments, the method includes the use of substituted replacements forhydrogen cyanide or formamide (HCONH₂) in which the substituent can beconverted to the hydrogen bound to carbon which ends up in the2-position. An example of such a replacement is ethyl cyanoformate whichformally can first dealkylate to give cyanoformic acid and then losecarbon dioxide to give hydrogen cyanide. For example, the method of theinvention can include reacting acetonitrile with formamide anddiphosgene to form 4,6-dichloropyrimidine. As a further example, themethod of the invention can include reacting acetonitrile with ethylcyanoformate and phosgene.

The solvent can optionally be an inert organic solvent, for examplechlorobenzene, or an excess of one of the raw materials, for exampleacetonitrile.

Reaction temperatures can be in the range of 0° C. to 160° C.,preferably 60° C. to 120° C., and most preferably 100° C. to 110° C.

The reaction is typically carried out in a sealed vessel underautogenous pressure. Alternatively, the reaction may be carried outusing appropriate equipment under controlled pressure of 0 to 800 psig,preferably 100 to 300 psig, and most preferably 150 to 250 psig.

The process of the invention results in preferential formation of thedesired chlorinated pyrimidine (i.e., the cross condensation product)relative to formation of the chlorinated pyrimidine substituted at the 2position (i.e., the self condensation product). In particular, it issurprising to observe that reaction of formamidoyl chloride or itsequivalents with acetamidoyl chloride or its equivalents favors theproduction of 4,6-dichloropyrimidine, the cross-coupling product, overthe production of 2-methyl-4,6-dichloropyrimidine, the self condensationproduct from acetonitrile. For example, an equimolar mixture of the two(formamidoyl chloride or equivalent with acetamidoyl chloride orequivalent) is expected to give the statistical 1:1 distribution of4,6-dichloropyrimidine and 2-methyl-4,6-dichloropyrimidine. In contrasta distribution of approximately 10:1 is typically observed favoring4,6-dichloropyrimidine itself. Similarly, when a large excess ofacetonitrile relative to formamidoyl chloride is used, the product ratioindicates that the cross-condensation product is preferentially formed.For example, when a 37:1 molar ratio of acetonitrile to formamidoylchloride is used, the ratio of 4,6-dichloropyrimidine to2-methyl-4,6-dichloropyrimidine is approximately 1:1.4. In a statisticaldistribution of products, a ratio of 1:37 would be expected.

All of the embodiments described above can also be used for thepreparation of 4-chloro-6-hydroxypyrimidine by limiting the amount ofphosgene (or its replacement) or by conducting the reaction at lowtemperatures.

All of the embodiments described above can also be used for thepreparation of certain 5-substituted-4,6-dichloropyrimidines by usingappropriately substituted amides or nitrites. For example, the method ofthe invention can include reacting butyronitrile and formamide withhydrogen chloride and phosgene (or its replacement) to form5-ethyl-4,6-dichloropyrimidine.

All of the embodiments described above can also be used for thepreparation of 5-substituted-4-chloro-6-hydroxypyrimidine by usingappropriately substituted amides or nitriles and by limiting the amountof phosgene (or its replacement) or by conducting the reaction at lowtemperatures.

The chlorinated pyrimidines produced by the method of the invention canbe used to synthesize commercially or medically important compounds. Forexample, the chlorinated pyrimidines, especially 4,6-dichloropyrimidine,can be used to make pesticides, and/or pharmaceuticals, such asnucleoside analogs and compounds that are active on the central nervoussystem (CNS) of animals and humans.

Additional objects and advantages of the invention will be set forth inpart in the description which follows, and in part will be obvious fromthe description, or may be learned by practice of the invention. Theobjects and advantages of the invention will be realized and attained bymeans of the elements and combinations particularly pointed out in theappended claims.

DETAILED DESCRIPTION

Reference will now be made in detail to the preferred embodiments of thepresent invention. While the following detailed description relates topreferred embodiments of the invention, the invention is not limited inscope to the specific details provided below, but encompasses the entirescope disclosed and claimed herein, including all obvious variationsthat can be made by those skilled in the art.

The present invention relates to methods of synthesizing4,6-dichloropyrimidine, 4-chloro-6-hydroxypyrimidine,5-substitituted-4,6-dichlorpyrimidines, and5-substituted-4-chloro-6-hydroxypyrimidines from imidoyl chloridecompounds. The present invention contemplates use of starting materialsthat can be converted to imidoyl chlorides in situ under reactionconditions. Such starting materials include mixtures of nitrites andHCl, as well as mixtures of amides and phosgene. The present inventionincludes the use of phosgene as well as replacements for phosgene thatreact equivalently, for example diphosgene. The chemical structures of4,6-dichloropyrimidine, 4-chloro-6-hydroxypyrimidine,5-substituted-4,6-dichlorpyrimidines, and5-substituted-4-chloro-6-hydroxypyrimidines are:

The methods of synthesizing these compounds comprise reacting phosgene(COCl₂) (or its replacement) with imidoyl chloride compounds of theformula:

in which R¹ can be, independently, hydrogen or a C₁-C₁₂ hydrocarbylgroup, and at least one of the imidoyl chlorides must have two alphahydrogens. In the case where a 5-substituted-4,6-dichlorpyrimidine or a5-substituted-4-chloro-6-hydroxypyrimidine is formed, the 5 substituentis the same moiety as the R¹ moiety of the above imidoyl chloride. Theterm C₁-C₁₂ “hydrocarbyl group” refers to hydrocarbyl groups such asalkyl, alkenyl, alkynyl, alkoxy, aryl, and the like wherein saidhydrocarbyl group is optionally substituted with 1-5 (preferably 1 or 2)substituents. The substituents of the aliphatic moieties can be halo,aryl, alkoxy or the like, and the substituents of the aromatic moietiescan be halo, alkyl, alkoxy, alkenyl, alkynyl, or the like. Preferred areC₁-C₆ hydrocarbyl groups such as phenyl and lower alkyl, and morepreferred are C₁-C₃ hydrocarbyl groups, particularly alkyl groups suchas methyl, ethyl, propyl or isopropyl. The imidoyl chlorides can beprepared in situ by the reaction of a nitrile with HCl, or by thereaction of an amide with phosgene (or its replacement).

In the method of synthesis of chlorinated pyrimidines according to thepresent invention, two distinct imidoyl chloride compounds are reactedwith phosgene (or its replacement) to synthesize the desired chlorinatedpyrimidine. One or both of the imidoyl chloride compounds can besupplied pre-formed to the method of synthesizing chlorinatedpyrimidines according to the invention. Alternatively, both of theimidoyl chloride compounds can be synthesized as part of the method ofsynthesis of chlorinated pyrimidines according to the invention. Forexample, one or both of the imidoyl chloride compounds can besynthesized from organic amides or from organic nitrites. In oneembodiment of the present invention, one imidoyl chloride compound issynthesized from an organic amide while the other imidoyl chloride issynthesized from an organic nitrile. A general reaction scheme forsynthesis of 4-chloro-6-hydroxypyrimidines and 4,6-dichloropyrimidinesaccording to the invention is presented in Scheme 1. This includes theoptional formation of imidoyl chloride intermediates from both organicamides (e.g., formamide and acetamide) and organic nitrites (e.g.,hydrogen cyanide and acetonitrile)

As depicted in Scheme 1, cross-condensation of two different imidoylchloride compounds can produce an intermediate that can react withphosgene to produce a chlorohydroxypyrimidine. Thechlorohydroxypyrimidine so produced can then react with phosgene toproduce 4,6-dichloropyrimidines. If R₁ and R₂ are hydrogen atoms, themethod of the invention produces 4,6-dichloropyrimidine itself. If R₁ isother than hydrogen, the method of the invention produces5-substituted-4,6-dichloropyrimidines. For example, if R₁ is CH₂CH₃, themethod of the invention produces 5-ethyl-4,6-dichloropyrimidine. Theformation of chlorinated pyrimidines by cross-condensation of twodifferent imidoyl chloride compounds according to the methods disclosedherein were unknown at the time of the present invention.

In a first aspect of the invention, the method of synthesis ofchlorinated pyrimidines includes synthesis of two distinct imidoylchloride compounds by reacting two distinct organic amides with COCl₂(or its replacement), followed by cross-condensation of the two imidoylchloride compounds in the presence of phosgene (or its replacement) toform the desired chlorinated pyrimidine. Organic amides are generallyrepresented by the formula R—CONH₂. R₁, as shown in Scheme 1, can behydrogen or a hydrocarbyl group, but is preferably hydrogen or asubstituted or unsubstituted, linear or branched alkyl group. Thegeneral reaction for this embodiment of the invention is depictedschematically in Scheme 1 in which R₁ is chosen from among the R₁ groupsdisclosed above. If R₁ is other than hydrogen, the product issubstituted in the 5 position with R1. In a preferred embodiment, theorganic amides are unsubstituted alkylamides.

In a preferred embodiment of this aspect of the present invention, afirst organic amide is first reacted with phosgene (or its replacement).In certain embodiments of this aspect of the invention, the reaction isallowed to proceed only briefly before additional reactants are added tothe reaction mixture. In these certain embodiments, little or nodetectable product is produced before additional reactants are added. Inother embodiments of this aspect of the invention, the reaction isallowed to proceed until a substantial detectable amount of intermediateproduct is formed before additional reactants are added.

Once the first organic amide has reacted with phosgene (or itsreplacement) to the extent desired, a second organic amide, which is adifferent organic amide than the first organic amide, is added to thereaction mixture. The reactants are permitted to react for a sufficienttime to produce 4-chloro-6-hydroxypyrimidines and4,6-dichloropyrimidines if sufficient phosgene is present. In certainembodiments, the reaction is allowed to proceed until a substantialdetectable amount of 4,6-dichloropyrimidine is formed before thereaction is terminated.

In another embodiment of the present invention, a first organic amide isreacted with phosgene (or its replacement) to completion (i.e., to thepoint where all, or essentially all, of one or more of the reactants isused up) in a first reaction vessel. Similarly, a second organic amide,which may be different than the first organic amide, is reacted withphosgene to completion in a second reaction vessel. Upon completion ofthe respective reactions, the two reaction mixtures are combined to forma third reaction mixture. The reacting compounds in the third reactionmixture are permitted to react for a sufficient time to produce4-chloro-6-hydroxypyrimidines and 4,6-dichloropyrimidines if sufficientphosgene is used. In certain embodiments, the reaction is allowed toproceed until a substantial detectable amount of 4,6-dichloropyrimidineis formed before the reaction is terminated.

In yet another embodiment, a first and a second organic amide arecombined to form a first mixture containing reactants. Phosgene is addedto the first mixture to form a second mixture, and the mixture isreacted until 4-chloro-6-hydroxypyrimidine or 4,6-dichloropyrimidine (ifenough phosgene is used) is synthesized.

In a preferred embodiment of this aspect of the invention, the twoorganic amides are formamide and acetamide. Formamide and acetamide arereacted, separately or together, with phosgene (or its replacement) toform imidoyl chloride compounds, which are then converted to4,6-dichloropyrimidine by reaction with phosgene (or its replacement). Ageneral reaction scheme that accounts for the formation of4,6-dichloropyrimidine from formamide (R₂=H) and acetamide (R₁=H) ispresented in Scheme 1. In this reaction mechanism, formamide andacetamide are reacted, either partially or wholly, with phosgene (or itsreplacement) to produce imidoyl chloride intermediates. These imidoylchloride intermediates condense to form an intermediate that can reactwith phosgene (or its replacement) to form chlorohydroxypyrimidine.Chlorohydroxy-pyrimidine then reacts with phosgene (or its replacement)to produce 4,6-dichloropyrimidine, carbon dioxide (CO₂), and hydrogenchloride (HCl).

In a second aspect of the invention, the method of synthesis ofchlorinated pyrimidines includes reacting two distinct organic nitrilecompounds of formula R—CN with hydrogen chloride to form two distinctimidoyl chloride compounds, which are then converted to the desiredchlorinated pyrimidines by cross-condensation in the presence ofphosgene (or its replacement). R can be a hydrogen or a hydrocarbylgroup, but is preferably hydrogen or a substituted or unsubstituted,linear or branched alkyl group, preferably with less than 8 carbons,provided that one of the nitrile compounds must have 2 alpha hydrogens,for example, butyronitrile. The general reaction for this embodiment ofthe invention is depicted schematically in Scheme 1 in which R₁ ischosen from among the R₁ groups disclosed above. In preferredembodiments, the organic nitrites are unsubstituted alkyl nitrites.

In a third aspect of the invention, the method of synthesis ofchlorinated pyrimidines includes reacting a distinct organic nitrilecompound of formula R—CN with hydrogen chloride to form a distinctimidoyl chloride compound, which is cross-condensed with formamidoylchloride (produced by the reaction of formamide and phosgene or itsreplacement) in the presence of phosgene (or its replacement) to producethe desired chlorinated pyrimidines. R can be a hydrocarbyl group, butis preferably a substituted or unsubstituted, linear or branched alkylgroup, preferably with less than 8 carbons, provided that the nitrilecompound has 2 alpha hydrogens, for example, butyronitrile. In preferredembodiments, the organic nitrile is an unsubstituted alkyl nitrile.

In a fourth aspect of the invention, the method of synthesis ofchlorinated pyrimidines includes reacting a distinct organic amidecompound of formula R—CONH₂ with phosgene (or its replacement) to form adistinct imidoyl chloride compound, which is cross-condensed withformamidoyl chloride (produced by the reaction of hydrogen chloride andhydrogen cyanide) in the presence of phosgene (or its replacement) toproduce the desired chlorinated pyrimidines. R can be a hydrocarbylgroup, but is preferably a substituted or unsubstituted, linear orbranched alkyl group, preferably with less than 8 carbons, provided thatthe amide compound has 2 alpha hydrogens, for example, butyramide. Inpreferred embodiments, the organic amide is an unsubstituted alkylamide.

In each of the above variations, where the desired product is a2-unsubstituted pyrimidine, the raw material contributing the carbon atthe 2-position (generally HCN or formamide in the above discussion) hasexactly one hydrogen attached to this carbon. In each variation, thissingle hydrogen attached to carbon in the raw material may be replacedby a group which can be converted to hydrogen. This is shown in Scheme2, which depicts a variation of the general mechanism of Scheme 1 inwhich a replacement for the HCN or formamide is used. In place ofhydrogen cyanide or formamide (R₂=H), a substituted replacement (R₃) maybe used wherein the substituent may be converted to H. The conversion ofsubstituent R₃ to H may take place as the initial step in the process(to give hydrogen cyanide or formamide) or at any intermediate stage(e.g., to give the 4-chloro-6-hydroxypyrimidine) or at the final stage(to give the dichloropyrimidine). As an example, ethyl cyanoformate(R₂=CO₂Et) may react with HCl to give HCN, CO₂ and EtCl as the firststep in the process. Examples of R₃ which may be converted to H includealkoxycarbonyl (ethyl cyanoformate), alkoxylsulfinyl, trimethylsilyl,hydoxymethyl derivatives (e.g, acetone cyanohydrin), etc.

The following examples are to illustrate the invention, but should notbe interpreted as a limitation thereon.

EXAMPLES Example 1 General Procedure for Synthesis of4,6-dichloropyrimidine from Amides and Nitrites

A Hastelloy C accelerating rate calorimetry (ARC) sphere is charged withreactants and attached to the ARC. The mixture is heated underautogenous pressure. A pressure transducer is used to monitor thepressure in the ARC sphere during the course of synthesis. After thedesired reaction time, the ARC sphere is allowed to cool to roomtemperature (approximately 20° C.-25° C.). The residual pressure on thesphere is then vented through a caustic scrubber. Analysis of theproducts of the reactions is performed using liquid chromatography (LC)and gas chromatography/mass spectroscopy (GC/MS). Presence of4,6-dichloropyrimidine in the reaction products is confirmed bycomparison of the LC and GC/MS results with LC and GC/MS resultsobtained from an authentic sample of 4,6-dichloropyrimidine.

Liquid Chromatography Method for Analysis of 4,6-Dichloropyrimidine

Liquid Chromatograph: Hewlett-Packard 1100 liquid chromatograph with adiode array detector. Hewlett-Packard Chemstation 3D data analysissoftware.

Chromatography Column: Column=Highchrom HIRPB-250A; Packing=HighchromRPB; Length=25 cm; i.d.=4.6 mm.

HP 1100 Quaternary Pump:

Control: Flow=1.500 ml/min; Stop Time=23.00 min; Post Time=3.00 min

Solvents:

-   -   Solvent A: 20.0% (20% THF, 80% ACN)    -   Solvent B: 80.0% (0.5% H₃PO₄ in H₂O)    -   Solvent C: Off    -   Solvent D: Off

Timetable Time Solv. B Solv. C Solv. D Flow Pressure 0.00 80.0 0.0 0.01.500 400 13.00 80.0 0.0 0.0 1.500 400 14.00 1.0 0.0 0.0 1.500 400 17.001.0 0.0 0.0 1.500 400 18.00 80.0 0.0 0.0 1.500 400 23.00 80.0 0.0 0.01.500 400

HP 1100 Diode Array Detector:

Signals Signal Store Signal, Bw Reference, Bw [nm] A: Yes 250, 100 360,100 Retention Times:  2.87 minutes 4-chloro-6-hydroxypyrimidine 10.80minutes 4,6-dichloropyrimidineGas Chromatography/Mass Spectrometry Method for Analysis of4,6-Dichloropyrimidine

Gas Chromatograph: Hewlett-Packard 6890 gas Chromatograph with a massspectrometer detector. Hewlett-Packard Chemstation data analysissoftware.

Chromatography Column: Column=HP-5MS; Packing=Crosslinked 5% PH MESiloxane; Length=30 m; i.d.=0.25 mm; 0.25 micrometer film thickness.

Oven Conditions: Initial Temperature=75° C.; Initial Time=1.00 minute;Ramp Rate=25° C. per minute; Final Temperature=290° C.; Final Time=4.00minutes; Post Time=0.00 minutes; Run Time=13.60 minutes.

Inlet Conditions: Mode=splitless; Initial Temperature=250° C.;Pressure=8.8 psi; Purge Flow=50.0 mL/min; Purge Time=1.50 mL/min; TotalFlow=53.8 mL/min; Gas Saver=On; Saver Flow=20.0 mL/min; Saver Time=3.00min; Gas Type=Helium.

Column Conditions: Mode=Constant Flow; Initial Flow=1.0 mL/min; NominalInitial Pressure=8.8 psi; Average Velocity=58 cm/sec; OutletPressure=vacuum.

Mass Spectrometer Conditions: Solvent Delay=3.00 minutes; EMAbsolute=False; EM Offset=0; Resulting EM Voltage=2176.5; Low Mass=50;High Mass=550; Threshold=500; Sample #=3; MS Quad=150° C.; MSSource=230° C.

4,6-Dichloropyrimidine: Retention Time=3.27 minutes; m/e=148, 113, 86.

This general procedure was used in Examples 2-8, unless otherwiseindicated.

Example 2 Synthesis of 4,6-dichloropyrimidine from Formamide andAcetamide

0.001952 moles of formamide and 0.001947 moles of acetamide were mixedtogether with a solution of 0.007449 moles of phosgene in 4.2 gramschlorobenzene in an ARC sphere. The sphere was then attached to the ARCand the mixture was heated to 105° C. under autogenous pressure. Theabove reactants were permitted to react for 100 minutes at a maximumpressure of 250 psia. The formation of 4,6-dichloropyrimdine wasconfirmed by LC and GC/MS.

Example 3 Synthesis of 4,6-dichloropyrimidine from Formamide andAcetamide

0.000886 moles of formamide and 0.002979 moles of acetamide were mixedtogether with a solution of 0.007448 moles of phosgene in 4.2 gramschlorobenzene in an ARC sphere. The sphere was then attached to the ARCand the mixture was heated to 75° C. under autogenous pressure. Theabove reactants were permitted to react for 1390 minutes at a maximumpressure of 95 psia. The formation of 4,6-dichloropyrimdine wasconfirmed by LC and GC/MS.

Example 4 Synthesis of 4,6-dichloropyrimidine from Formamide andAcetamide

0.00248 moles of formamide and 0.00206 moles of acetamide were mixedtogether with a solution of 0.0078 moles of phosgene in 4.4 gramschlorobenzene in an ARC sphere. The sphere was then attached to the ARCand the mixture was heated to 105° C. under autogenous pressure. Theabove reactants were permitted to react for 1200 minutes at a maximumpressure of 268 psia. The formation of 4,6-dichloropyrimdine wasconfirmed by LC and GC/MS.

Example 5 Synthesis of 4,6-dichloropyrimidine from Formamide andAcetamide

0.00228 moles of formamide and 0.00235 moles of acetamide were mixedtogether with a solution of 0.008436 moles of phosgene in 4.2 gramschlorobenzene in an ARC sphere. The sphere was then attached to the ARCand the mixture was heated to 105° C. under autogenous pressure. Theabove reactants were permitted to react for 1080 minutes at a maximumpressure of 340 psia. The formation of 4,6-dichloropyrimdine wasconfirmed by LC and GC/MS.

Example 6 Synthesis of 4,6-dichloropyrimidine from Formamide andAcetamide

0.003248 moles of formamide and 0.001153 moles of acetamide were mixedtogether with a solution of 0.008631 moles of phosgene in 4.8 gramschlorobenzene in an ARC sphere. The sphere was then attached to the ARCand the mixture was heated to 105° C. under autogenous pressure. Theabove reactants were permitted to react for 1110 minutes at a maximumpressure of 280 psia. The formation of 4,6-dichloropyrimdine wasconfirmed by LC and GC/MS.

Example 7 Synthesis of 4,6-dichloropyrimidine from Formamide andAcetonitrile/HCl

0.00255 moles of formamide and 0.18 grams of acetonitrile/HCl were mixedtogether with a solution of 0.00795 moles of phosgene in 4.5 gramschlorobenzene in an ARC sphere. The sphere was then attached to the ARCand the mixture was heated to 105° C. under autogenous pressure. Theabove reactants were permitted to react for 1410 minutes at a maximumpressure of 227 psia. The formation of 4,6-dichloropyrimdine wasconfirmed by LC and GC/MS.

Example 8 Synthesis of 4,6-dichloropyrimidine from FormamideHydrochloride and Acetamide Hydrochloride

0.00123 moles of formamide hydrochloride and 0.00109 moles of acetamidehydrochloride were mixed together with a solution of 0.00869 moles ofphosgene in 4.9 grams chlorobenzene in an ARC sphere. The sphere wasthen attached to the ARC and the mixture was heated to 105° C. underautogenous pressure. The above reactants were permitted to react for5400 minutes at a maximum pressure of 290 psia. The formation of4,6-dichloropyrimdine was confirmed by LC and GC/MS.

Example 9 Synthesis of 4,6-dichloropyrimidine from Acetonitrile andFormamide

0.002021 moles of formamide were mixed together with a solution of0.005874 moles of phosgene in 3.1 grams acetonitrile in an ARC sphere.The sphere was then attached to the ARC and the mixture was heated to105° C. under autogenous pressure. The above reactants were permitted toreact for 180 minutes at a maximum pressure of 162 psia. The formationof 4,6-dichloropyrimdine was confirmed by LC and GC/MS.

Example 10 Synthesis of 4,6-dichloropyrimidine from Acetonitrile andFormamide

0.000735 moles of formamide were mixed together with a solution of0.005874 moles of phosgene in 3.1 grams acetonitrile in an ARC sphere.The sphere was then attached to the ARC and the mixture was heated to105° C. under autogenous pressure. The above reactants were permitted toreact for 180 minutes at a maximum pressure of 116 psia. The formationof 4,6-dichloropyrimdine was confirmed by LC and GC/MS.

Example 11 Synthesis of 5-ethyl-4,6-dichloropyrimidine fromButyronitrile and Formamide.

0.00196 moles of formamide were mixed together with a solution of0.005881 moles of phosgene in 3.1 grams butyronitrile in an ARC sphere.The sphere was then attached to the ARC and the mixture was heated to105° C. under autogenous pressure. The above reactants were permitted toreact for 180 minutes at a maximum pressure of 140 psia. The formationof 5-ethyl-4,6-dichloropyrimdine was confirmed by LC and GC/MS.

Example 12 Synthesis of 4,6-dichloropyrimidine in the Parr Reactor(17328-33)

A solution of 3.0536 g formamide and 33.1563 g acetonitrile was preparedand 33.1563 g of the solution was charged to a 100 ml Hastelloy-C Parrreactor equiped with valves for addition of materials and venting, acondenser, heating and stirring. The reactor was inerted with nitrogenand vented down to ambient pressure. Separately, 34 grams of phosgenewere condensed in a 150 ml stainless steel sampling cylinder.

The Parr reactor was sealed and heated to 124.9° C. using a heatingmantle with agitation. The reactor pressure built up to 19 psig. Liquidphosgene was charged to the reactor using 400 psig nitrogen. Thereaction temperature dropped immediately due to the addition of roomtemperature phosgene, but it rose to 140° C. within 10 minutes due toreaction. The combination of nitrogen pressure and reaction raised thereactor pressure to 320 psig within three minutes after phosgene wascharged, at which time vent line was opened to slowly bring the reactorpressure down to 200 psig. A Hastelloy C tubular condenser was used tokeep phosgene in the reactor. The highest pressure reached was 366 psigat four minutes after the phosgene charge. The temperature wascontrolled at 125° C. for three hour. The reactor was cooled down toroom temperature three hours after phosgene was charged.

The reaction mixture was collected and 102.9 g acetonitrile was used towash the reactor. The resulting 137.9 g slurry was filtered and washedwith acetonitrile to give 168.6 g filtrate and 12.25 g filter cake.Analysis of both the filtrate and filter cake gave 62.21% yield on4,6-dichloropyrimidine.

Example 13 Synthesis of 4,6-dichloropyrimidine from Ethylcyanoformatewith Acetonitrile and Phosgene

Preparation of saturated HCl-Acetonitrile mixture: To a 50 ml roundbottom flask equipped with a magnetic stirrer, diptube for phosgeneaddition, ipa-dry ice condenser, thermometer, heating mantle and causticscrubber was charged 35 gm (0.85 mole) of acetonitrile and anhydrous HClwas bubbled via diptube at a rate of 0.8 gm/min for about an hour atambient temperature. The saturated acetonitrile-HCl mixture collectedwas about 38 gms total.

Phosgenation Reaction: To the 50 round bottom flask containing 27 gms(0.6 mole) of the acetonitrile-HCl mixture prepared above was charged 23gms (0.23 mole) ethylcyanoformate. An additional 4 gm of HCl was bubbledthrough the mixture to insure HCl saturation. The mixture was heated to52° C. and then phosgene (17 gms) was bubble subsurface via the diptube.At end of the day the reaction was stripped of residual phosgene, cooledand allowed to stand overnight. The next day the mixture was heated foran additional 1.5 hrs at 74° C. The reaction mass was analysed by GC-MSwhich showed (TIC A %) 3.6% DCP. The presence of the DCP was confirmedby spiking the final reaction mass with an authentic DCP sample andcomparing the resulting GC-MS chromatograms.

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the practice of thisinvention without departing from the scope or spirit of the invention.Other embodiments of the invention will be apparent to those skilled inthe art from consideration of the specification and practice of theinvention disclosed herein. It is intended that the true scope andspirit of the invention is indicated by the following claims. Allreferences cited herein are hereby incorporated by reference in theirentireties.

1. A method of synthesizing 4,6-dichloropyrimidine,5-substituted-4,6-dichloropyrimidines, 4-chloro-6-hydroxypyrimidine, or5-substituted-4-chloro-6-hydroxypyrimidines, said method comprisingreacting a first imidoyl chloride compound represented by the formula:

wherein R₂ is hydrogen, C₁₋₄ alkoxycarbonyl, C₁₋₄alkoxysulfinyl,trimethylsilyl or a group —C(OH)′R″ wherein R′ and R″ are independentlyhydrogen, C₁₋₄alkyl or phenyl, and a second imidoyl chloride compoundwhich has two alpha hydrogens represented by the formula:

wherein R₁ is selected from hydrogen and a C₁-C₁₂ hydrocarbyl group,with phosgene, diphosgene, triphosgene or oxalyl chloride.
 2. The methodof claim 1, R₁ is hydrogen.
 3. The method of claim 1, wherein R₁ is aC₁-C₃ alkyl group.
 4. The method of claim 1, R₁ is methyl.
 5. The methodof claim 1, wherein R₂ is hydrogen.
 6. The method of claim 1, wherein R₂is ethoxycarbonyl.
 7. The method of claim 1, wherein the first andsecond imidoyl chloride compounds are reacted with phosgene.
 8. Themethod of claim 1, further comprising synthesizing said first imidoylchloride compound and said second imidoyl chloride compound, providedthat one of the imidoyl compounds has 2 alpha hydrogens, by reaction of:a) at least one organic amide of structure R—CONH₂ with phosgene,diphosgene, triphosgene or oxalyl chloride, or b) at least one organicnitrile of structure R—CN with hydrogen chloride, or c) both at leastone organic amide of structure R—CONH₂ with phosgene, diphosgene,triphosgene or oxalyl chloride and at least one organic nitrile ofstructure R—CN with hydrogen chloride; wherein each R group is,independently, hydrogen or a group which can be converted to hydrogen ora C₁-C₁₂ hydrocarbyl group.
 9. The method of claim 8, wherein said groupR is a substituted or unsubstituted, linear or branched alkyl group. 10.The method of claim 8, wherein one organic nitrile is butyronitrile. 11.The method of claim 8, wherein one organic nitrile is acetonitrile. 12.The method of claim 8, wherein the process is carried out in an inertorganic solvent.
 13. The method of claim 8, wherein the process iscarried out in an excess of nitrile.
 14. The method of claim 8, whereinthe process is carried out in an excess of phosgene.
 15. The method ofclaim 8, wherein the process is carried out in an excess of amide. 16.The method of claim 8, wherein the process is carried out in stages withthe formation of imidoyl chlorides, either separately or as a mixture,being done and then a mixture of the imidoyl chlorides is treated withphosgene to generate the products.
 17. The method of claim 8, whereinthe process is carried out in one stage with the formation of imidoylchlorides being done concurrently with treatment by phosgene to generatethe products.
 18. The method of claim 8, wherein the process is carriedout with continuous feed of raw materials into a reactor system andoutflow and recovery of product.
 19. The method of claim 8, wherein theprocess is carried out in batches with discreet steps for charging rawmaterials and recovery of product.
 20. The method of claim 8, whereinthe process is carried out at 0° C. to 300° C.
 21. The method of claim8, wherein the process is carried out at 60° C. to 160° C.
 22. Themethod of claim 8, wherein the process is carried out at 80° C. to 130°C.
 23. The method of claim 8, wherein the process is carried out atpressures of 0 to 800 psig.
 24. The method of claim 8, wherein theprocess is carried out at pressures of 100 to 300 psig.
 25. The methodof claim 8, wherein the process is carried out at pressures of 150 to250 psig.
 26. A method of synthesizing 4,6-dichloropyrimidine,5-substituted-4,6-dichloropyrimidines, 4-chloro-6-hydroxypyrimidine, or5-substituted-4-chloro-6-hydroxypyrimidines, said method comprisingreacting a first imidoyl chloride compound represented by the formula:

wherein R₂ is —C(OH)R′R″ wherein R′ and R″ are independently hydrogen,C₁₋₄ alkyl or phenyl, and a second imidoyl chloride compound which hastwo alpha hydrogens represented by the formula:

R₁ is selected from hydrogen and a C₁-C₁₂ hydrocarbyl group, withphosgene, diphosgene, triphosgene or oxalyl chloride.
 27. The method ofclaim 26, wherein R₂ is C₁₋₄ alkoxycarbonyl, C₁₋₄ alkoxysulfinyl,trimethylsilyl or a group —C(OH)R′R″ wherein R′ and R″ are independentlyhydrogen, C₁₋₄ alkyl or phenyl.
 28. The method of claim 26, wherein R₂is C₁₋₄ alkoxycarbonyl or C₁₋₄ alkoxysulfinyl.
 29. The method of claim26, wherein R₂ is ethoxycarbonyl.
 30. A method of synthesizing4,6-dichloropyrimidine, 5-substituted-4,6-dichloropyrimidines,4-chloro-6-hydroxypyrimidine, or5-substituted-4-chloro-6-hydroxypyrimidines, said method comprisingreacting a first imidoyl chloride compound represented by the formula:

wherein R₂ is hydrogen, —C(OH)R′R″ wherein R′ and R″ are independentlyhydrogen, C₁₋₄ alkyl or phenyl, and a second imidoyl chloride compoundwhich has two alpha hydrogens represented by the formula:

wherein R₁ is selected from hydrogen and a C₁-C₁₂ hydrocarbyl group,with diphosgene, triphosgene or oxalyl chloride.
 31. The method claim30, wherein the first and second imidoyl chloride compounds are reactedwith oxalyl chloride.
 32. The method of claim 30, wherein the first andsecond imidoyl chloride compounds are reacted with diphosgene ortriphosgene.